Submissions for variant NM_000179.3(MSH6):c.2419G>A (p.Glu807Lys)

gnomAD frequency: 0.00001  dbSNP: rs587779923

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656895	SCV000149299	uncertain significance	not provided	2022-07-14	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with early-onset colorectal cancer, an individual with glioblastoma multiforme, and an individual with breast cancer who also carried a pathogenic BRCA1 variant (Lu et al., 2015; DeRycke et al., 2017; Cock-Rada et al., 2018); This variant is associated with the following publications: (PMID: 32980694, 28528518, 26689913, 28944238, 31658756, 17531815, 21120944, 31104363)
Invitae	RCV000199520	SCV000254296	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000409470	SCV000488055	uncertain significance	Lynch syndrome 5	2015-12-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000491756	SCV000580212	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-05	criteria provided, single submitter	clinical testing	The p.E807K variant (also known as c.2419G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 2419. The glutamic acid at codon 807 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in a cohort of 85 Colombian women with breast cancer; however, this individual was also noted to carry a pathogenic BRCA1 mutation (Cock-Rada AM et al. Fam. Cancer, 2018 01;17:23-30; Urbina-Jara LK et al. Genes (Basel), 2019 10;10). This alteration was also detected in 1/1231 colorectal cancer patients and 0/93 controls (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000115390	SCV000601532	uncertain significance	not specified	2017-04-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000491756	SCV000685285	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 807 of the MSH6 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with colorectal cancer (PMID: 28944238), and in an individual affected with breast cancer who also carried a BRCA1 truncation variant (PMID: 28528518, 31658756). This variant has been identified in 3/281820 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV000656895	SCV000805867	uncertain significance	not provided	2016-12-16	criteria provided, single submitter	clinical testing
Mendelics	RCV000708875	SCV000837897	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765687	SCV000897029	uncertain significance	Endometrial carcinoma; Mismatch repair cancer syndrome 1; Lynch syndrome 5	2018-10-31	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000409470	SCV004019027	likely benign	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001249960	SCV001423974	uncertain significance	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing